How Does It Pump, and Why Does It Fail?
Scientist and surgeon collaborate to understand the heart's complex biochemistry
Babies fall asleep lulled by its steady rhythm. Doctors monitor it for signs
of disease. If you listen carefully in a quiet room, you can hear its reassuring
sound, even without a stethoscope. What you can't hear is the complex biochemistry
behind the beating of a human heart.
Frank Pagani, Margaret Westfall and Sharlene
Day Photo: Martin Vloet |
Margaret Westfall, Ph.D., an assistant professor of cardiac surgery in the
U-M Cardiovascular Center, is trying to decipher these biochemical signals
by studying proteins that modulate the contractions of individual cardiac muscle
cells called myocytes. It is the coordinated action of millions of individual
myocytes that make it possible for the entire heart muscle to contract and
relax in rhythm — allowing it to pump blood through the body.
Basically, myocytes contract when calcium ions are released in the cell and
relax when calcium is removed. But there's a lot of complicated biochemistry
required to keep all that calcium moving to the right place at the right time.
This biochemistry is the focus of intense investigation by scientists.
Westfall focuses on several proteins involved in this process. One of them
is called protein kinase C, or PKC for short. "We know there are about 12 variations
called PKC isoforms, and that each isoform acts on a different group of proteins
within the cell to modulate the heart's pumping action," Westfall says. "Myocytes
from healthy hearts contain different isoforms than myocytes from diseased
hearts. One of the questions we hope to answer in our research is what is the
relationship between specific PKC isoforms and contractile function during
the development of cardiac hypertrophy or heart failure?"
Unlike most muscle cells, myocytes can't divide to make new copies. So when
the heart has to work harder for long periods of time — as happens with high
blood pressure or to compensate for heart attack damage — it can't just make
more cells. Instead, existing heart muscle cells grow larger, a condition doctors
call hypertrophy. This causes the heart's muscular wall to thicken and the
heart to enlarge, which eventually makes the heart less effective at pumping
blood. Over time, heart muscle dies, scar tissue forms, and the heart gets
weaker. The result is progressive heart failure, a condition that affects almost
5 million Americans."
"One problem for many people in heart failure is that it takes too long for
myocytes to relax," Westfall explains. "Stiffness increases as the heart progresses
into failure, and results in an impaired ability of the heart to relax completely
with each beat. We don't understand all the components of the diastolic or
relaxation phase yet, but we believe it is modulated by PKC."
To obtain the human myocytes she needs for her research, Westfall works closely
with Sharlene Day, M.D. (Residency 1998), a lecturer in cardiology, and Francis
Pagani, M.D. (Residency 1996), Ph.D., an associate professor of surgery who
leads the U-M's Heart Transplant Program. Pagani treats some advanced stage
heart failure patients by surgically implanting a heart-assist pump, which
takes pressure off the deteriorating heart muscle and partially restores heart
function. To implant the pump, Pagani must remove a nickel-sized plug of heart
tissue. Westfall and Day study myocytes from this tissue, or from the patient's
own diseased heart after the patient receives a heart transplant.
"As a scientist, the advantage of collaborating with surgeons is that it lets
us compare PKC isoforms in myocytes from the same patient before and after
the heart-assist pump is implanted," Westfall says. The long-term goal of Westfall's
research is to develop gene transfer technology capable of delivering genes
and proteins to restore normal function in failing myocytes.
"A unique feature of the new Cardiovascular Center is that it will bring scientists
and surgeons together in one facility making it easier for them to develop
more collaborative research studies between researcher and clinician," says
Richard Prager, who directs adult cardiac surgery at the U-M Cardiovascular
Center. "Collaborations like this are especially important, because they help
translate scientific discoveries in the laboratory into new treatments and
therapies for people with cardiovascular disease."
-SFP
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How Does It Pump, and Why Does It Fail?
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